Istamycin A or B is a new aminoglycosidic antibiotic discovered by the present inventors and is represented by the formula: ##STR1## wherein R.sup.1 is a hydrogen atom and R.sup.2 is an amino group for istamycin A, or R.sup.1 is an amino group and R.sup.2 is a hydrogen atom for istamycin B (see Japanese Patent Application "Kokai" No. 145697/80; U.K. Patent Application GB 2048855A; U.S. Patent Application Ser. No. 141,492 now U.S. Pat. No. 4,296,106). Istamycin A or B is known to exhibit a high antibacterial activity against a wide range of gram-negative and gram-positive bacteria.
It is also known that a few of aminoglycosidic antibiotic substances are converted to an N-methanesulfonic acid derivative thereof by N-sulfomethylation of some or all of the amino group(s) present in the molecule, and that the N-methanesulfonic acid derivative so produced exhibits a lower toxicity than the parent antibiotic. An example of this is N-methanesulfonic acid derivatives of kanamycin A (Journal of Antibiotics, A 14, page 170 (1961)). Besides, it has been found by the present inventors that an N-methanesulfonic acid derivaive of 3',4'-dideoxykanamycin B can be synthetized by interaction of 3',4'-dideoxykanamycin B, an aldehyde and sulfurous acid or an alkali metal hydrogen sulfite, and that this N-methanesulfonic acid derivative is of lower toxicity than 3',4'-dideoxykanamycin B and hence is valuable for therapeutic treatment of bacterial infections (see Japanese Patent Application "Kokai" No. 39653/77; U.K. Patent No. 1507118; U.S. Pat. No. 4,091,202). Recently, it has also been reported that a less toxic N-methanesulfonic acid derivative of fortimycin antibiotic may be obtained as a new substance having useful antibacterial activity (see Japanese Patent Application No. 38301/80).
Accordingly, if a new antibiotic derivative of istamycin A or B which shows a lower toxicity than istamycin A or B itself is provided, it will increase the applications of istamycin A or B and make this antibiotic substance more valuable.
An object of this invention is to provide a new antibiotic derivative of istamycin A or B which retains the useful antibacterial activity of istamycin A or B but exhibits a lower toxicity than that of istamycin A or B. The other object is to provide a process for the preparation of such new antibiotic derivative of istamycin A or B. Another objects of this invention will be clear from the following descriptions.
As a result of extensive research, we, the present inventors, have now found that as new compounds, N-methanesulfonic acid derivatives of istamycin A or B can be synthetized by reaction of istamycin A or B of the above formula (I) with an aldehyde of the formula: EQU RCHO (III)
wherein R is as defined later and also with sulfurous acid or an alkali or alkaline earth metal hydrogen sulfite (including ammonium hydrogen sulfite) of the formula: EQU MHSO.sub.3 (IV)
wherein M is a hydrogen atom, an alkali metal, alkaline earth metal atom or ammonium cation. We have confirmed that these N-methanesulfonic acid derivatives of istamycin A or B are of remarkedly lower toxicity than istamycin A or B. Istamycin A or B contains three amino groups and one methylamino group per molecule as will be clear from the above formula (I), and it has been found that the new N-methanesulfonic acid derivative of istamycin A or B prepared is the one in which one, two, three or four groups amongst the aforesaid three amino groups and one methylamino group present in the molecule is (are) N-sulfomethylated, that is to say, substituted with a methanesulfonate group of the formula: EQU --CHRSO.sub.3 M (II)
wherein R is a hydrogen atom, an alkyl group, preferably an alkyl group of 1.about.4 carbon atoms, a substituted alkyl group, phenyl group or a substituted phenyl group, and M represents a hydrogen atom, an ammonium cation, an alkali metal or an alkaline earth metal atom. The total number of the N-sulfomethylated amino and methylamino groups present in the resulting N-methanesulfonic acid derivative of istamycin A or B amounts to 1, 2, 3 or 4, depending upon the molar proportions of the aldehyde and the sulfurous acid or sulfite compound employed for 1 molar proportion of istamycin A or B.